Phenytoin follows zero-order kinetics at therapeutic doses because its metabolism saturates hepatic enzymes. The clinical implication is:
- A Small dose increases produce proportional and predictable plasma level increases
- B Phenytoin has a very short half-life because zero-order kinetics accelerate elimination
- C Small dose increases at therapeutic levels cause disproportionately large plasma level rises, necessitating small incremental dose adjustments ✓
- D Phenytoin's clearance increases linearly with dose, making high-dose therapy safe
Explanation
Phenytoin undergoes Michaelis-Menten (saturable) kinetics; at therapeutic concentrations the CYP2C9/2C19 enzymes responsible for its hydroxylation are near-saturated, so a small dose increase dramatically decreases clearance and causes a disproportionate (non-linear) rise in plasma concentration into the toxic range. This narrow therapeutic index combined with non-linear kinetics means dose titration must be done in small steps (25–50 mg increments) with careful monitoring. This is different from true zero-order kinetics (constant rate of elimination regardless of concentration, as seen with ethanol at high doses).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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